We have previously demonstrated limitation in coronary flow reserve of the coronary microcirculation to be a frequent mechanism of myocardial ischemia and angina pectoris in patients with angiographically normal epicardial coronary arteries. We have further found that limited coronary flow reserve can be demonstrated during rapid atrial pacing, especially after ergonovine administration, associated with angina pectoris and metabolic and hemodynamic evidence of myocardial ischemia. Because ergonovine administration increases coronary resistance without discernible changes in the epicardial coronary arteries, our hypothesis is that ergonovine in inducing vasoconstriction of the coronary microcirculation, resulting in limited flow reserve to stress. Because pacing does not allow assessment of total transmural coronary flow reserve, a potent coronary arteriolar vasodilator, dipyridamole, was used to investigate peak transmural flow reserve in patients with anginal pain despite normal epicardial coronary arteries. Twenty-five patients were identified as having limited flow reserve during the stress of rapid atrial pacing following administration of ergonovine and an additional 15 patients were felt not to have evidence of coronary vasoconstriction after ergonovine administration. After administration of dipyridamole 0.5 to 0.75 mg/kg intravenously, the lowest absolute levels to which coronary resistance fell and the maximum absolute levels to which great cardiac vein flow rose were impaired in the 25 patients with ergonovine-induced flow limitation compared to the 15 patients without limitation after ergonovine administration. These studies suggest that patients with anginal chest pain despite normal epicardial coronary arteries may have exaggerated coronary responses to vasoconstrictor stimuli, which can result in myocardial ischemia during stress, as well as attenuated responses to coronary vasodilator stimuli.